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1.  Therapy of unspecific tinnitus without organic cause 
There is a variety of medical and non-medical therapies in practice, which were not evaluated regarding its effectiveness by any systematic evidence oriented investigation.
A number of therapies of medical and non-medical type try to treat the different types of tinnitus. The evidence in the scientific literature also had to be cleared in the field of diagnosis and classification as well as medical/psychiatric/psychological procedures of existing medical therapy.
The HTA report had to investigate the following questions:
Which evidence do diagnostic methods in recognition of tinnitus have? Which types of therapy show medical effectiveness at the acute or chronic tinnitus without an organic cause? Which consequences (need for further research, future procedures) can be drawn?
In the following databases "tinnitus" was searched according to the search string:
HTA97; INAHTA; CDAR94; CDSR93; CCTR93; ME66; ME0A; HT83; SM78; CA66; CB85; BA70; BA93; EM74; IS74; ET80; EB94; IA70; AZ72; CV72; GE79; EU93; HN69; ED93; EA08
Result: 1932 studies, unsorted after assessment in accordance with EBM criterions, selection: 409 studies.
Due to the completely heterogeneous representation modes of the therapeutic approaches at the treatment of the chronic tinnitus no quantitative synthesis method could be performed. Therefore the methodology of a qualitative overview has been carried out.
The diagnostic confirmation of the non-specific tinnitus without organic cause meets with the problem of the assurance of the diagnosis tinnitus. According to the current opinion the stepwise diagnostics is carried out also in the case of the so called subjective tinnitus. Nothing can be said about the evidence of these procedures since no publication was found about that. A study concerning the evidence of the diagnostic questionnaires from Goebel and Hiller [1] comes to the end that the tinnitus questionnaire frequently used (TF) [2] is the best evaluated procedure.
The number of therapies which treat tinnitus is exceptionally high and makes clear, that the search for "the" tinnitus therapy is still going on. According to the current knowledge tinnitus genesis is multifactorial and therefore there can’t be any standard therapy for tinnitus. The following seven categories can be distinguished:
Ad 1: Machine-aided acoustic therapies
From many studies regarding machine-aided acoustic therapy of tinnitus only two showed an evidence degree that allows scientifically correct statements about the effectiveness of these procedures. Selectively significant improvements could be shown in the comparison with a placebo (apparatus switched off) a superiority of tinnitus-maskers.
Ad 2: Electrostimulation
In an application study of electro-stimulation the results were not evaluated statistically, but it was described descriptively that a successful medical treatment can be expected in about 50% of the cases.
Ad 3: Psychological therapy procedures
Hypnosis did not show positive effectiveness. With regard to biofeedback it can be concluded that this method can be effective in individual cases, however regarded as unreliable from missing reproducibility. Neurobiofeedback could prove that it had a positive therapeutic effect.
From eight controlled studies to relaxation techniques and cognitive behaviour therapy four studies showed a therapeutic effectiveness and four failed. Combined therapies proved generally to be more effective than individual types.
The behaviour medical psychotherapy could show a positive therapy effect. In a study with cognitive therapy and relaxation (three groups, a passive relaxation, an active relaxation and a cognitive therapy) short-term successes could be stated (for one month), however, the parameters of success returned on the initial value after four months.
Also only coincidental and short-term successes could be achieved with cognitive behaviour therapy training, autogenic training and structured group psychotherapy.
Ad 4: Tinnitus Retraining Therapy (TRT)
Unfortunately, the published results of the TRT are methodically frequently bad and scientific of a poor value. Many of the studies presented until now regarding tinnitus retraining therapy are not informative in their scientific context.
In a study with 95 patients with a chronic tinnitus TRT could show a significant, more than six months lasting stable success by comparison to a combination of TET with group behaviour therapy (improvement be achieved around at least ten points in the tinnitus questionnaire (TF)).
Ad 5: Pharmacological therapies
Rheological drugs (medicines for hemodilution) could not show any statistically significant effect in the treatment of tinnitus.
Studies to the medical treatment with tocainides (lidocaine) showed repeatable positive effects on tinnitus in higher dosages (as of 1.2 mg/day). Lamotrigine as a medicine had an effect positively only at with a small fraction of patients. Two studies with GABA receptor agonists could not prove therapeutic effects for tinnitus. Undesired side-effects were observed. Injections with Carvoverine (a glutamate antagonist) achieved significantly successes with a special form of tinnitus, the “Cochlear-synaptic tinnitus (CST)".
A tricyclic antidepressant (Amitriptilin) could prove superiority against placebo. This effect could be confirmed in another study. However Clonazepame (a benzodiazepine), could not achieve any improvement. Short-term improvements were achieved with other benzodiazepines (Clonazepame, Diazepam, Flurazepame, Oxacepame and Alprazolame).
A German retrospective study suggests a graded pharmacological therapy by means of rheological infusion therapy, applications of neurotransmitters, and injections of lidocaine. This method achieved a disappearance or a recovery of the complaints at 95.3% of the acute and 26.7% of the chronic cases.
Ad 6: Surgical procedures
The effects of the operative excision of the stapes (stapedectomy) showed significant effects concerning tinnitus. This method is a routine operation to recover hearing, effects on tinnitus were observed only coincidently.
There are generally high frequencies of improvements of tinnitus after cochlea implantations; however the risk of deterioration is present with this method.
Ad 7: Other and alternative therapy procedures
The hyperbaric oxygen therapy can be considered successful after acute events with tinnitus. The therapy should be started in the first month after appearance of the tinnitus.
The methods transcranial-, electromagnetic and transcutaneous nerve stimulations did not show any significant effects on tinnitus. Also low laser medical treatment showed disappointing effects.
The “pneumatic external contra-pulsation” is described as an unproblematic usable procedure by the authors of the examination, but 10% of the patients had to stop the medical treatment because of complications associated with the medical treatment.
Acupuncture showed significant improvements in comparison to medical treatment. The effectiveness of this therapy could not be reproduced in another study. Five other studies between 1993 and 1999 also did not show any therapeutic effect of this method. Gingko-Biloba preparations did not show any positive effects in large-scale studies on tinnitus.
Neither the diagnostic procedures nor the therapeutic methods or the individual therapies reach a usual scientific level in medicine. Unsolved problems concerning insurance, economic as well as legal problems have resulted for the patients and for caring stuff from this unsatisfactory situation.
Numerous competitive tinnitus emergence models led to an incredible creativity in trying out different therapy approaches. No convergence of the therapy procedures can be seen within the last decades of tinnitus research, contrariwise there is always more and more “creativity” of new approaches.
Priority has to be given to find the cause of tinnitus since therapies are a consequence of a better understanding of these symptoms that evidence oriented investigations on an usual scientific level can be started.
The innumerable therapeutic approaches, seeming completely incoherent to their effects should be coordinated on the meaningfulness, on the success parameters and with patient safety in light of the most plausible explanation models for non-specific chronic Tinnitus. To this the facilities of competence centres or related science- directing facilities are recommendable.
Examinations which are carried out also with small numbers show often methodical insufficiencies. It is necessary that minimal requirements on a scientifically clinical experiment, such as design, case number calculation, analytic statistics, control group, are fulfilled.
It is recommendable, that further research has to be promoted regarding tinnitus causes that a coordinated evidence-orientated treatment will be developed.
PMCID: PMC3011356  PMID: 21289968
2.  Effectiveness and Cost Effectiveness of Expanding Harm Reduction and Antiretroviral Therapy in a Mixed HIV Epidemic: A Modeling Analysis for Ukraine 
PLoS Medicine  2011;8(3):e1000423.
A cost-effectiveness study by Sabina Alistar and colleagues evaluates the effectiveness and cost effectiveness of different levels of investment in methadone, ART, or both, in the mixed HIV epidemic in Ukraine.
Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine—chosen in this study as a representative country—IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.
Methods and Findings
We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.
Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics.
Please see later in the article for the Editors' Summary
Editors' Summary
HIV epidemics in Eastern Europe and Central Asia are mainly driven by increasing use of injection drugs combined with heterosexual transmission. In the Ukraine, in 2007, there were 82,000 officially registered people living with HIV—three times the number registered in 1999—and an estimated 395,000 HIV infected adults. The epidemic in Ukraine, like other countries in the region, is concentrated in at-risk populations, particularly people who inject drugs: in 2007, an estimated 390,000 Ukrainians were injecting drugs, an increase in drug use over the previous decade, not only in Ukraine, but in other former USSR states, owing to the easy availability of precursors for injection drugs in a climate of economic collapse.
The common practices of people who inject drugs in Ukraine and in other countries in the region, such as social injecting, syringe sharing, and using common containers, increase the risk of transmitting HIV. Public health interventions such as needle exchange can limit these risk factors and have been gradually implemented in these countries. In 2007, Ukraine approved the use of methadone substitution therapy and the current target is for 11,000 people who inject drugs to be enrolled in substitution therapy by 2011. Furthermore, since treatment for HIV-infected individuals is also necessary, national HIV control plans included a target of 90% antiretroviral therapy (ART) coverage by 2010 but in 2007 less than 10% of the 91,000 eligible people received treatment. Although the number of people who inject drugs and who receive ART is unknown, physicians are often reluctant to treat people who inject drugs using ART owing to alleged poor compliance.
Why Was This Study Done?
As resources for HIV interventions in the region are limited, it is important to investigate the appropriate balance between investments in methadone substitution therapy and ART in order to maximize benefits to public health. Several studies have analyzed the cost effectiveness of methadone substitution therapy in similar settings but have not considered tradeoffs between ART and methadone substitution therapy. Therefore, to provide insights into the appropriate public health investment in methadone substitution therapy and ART in Ukraine, the researchers evaluated the public health effectiveness and cost effectiveness of different strategies for scaling up methadone substitution therapy and/or expanding ART.
What Did the Researchers Do and Find?
The researchers developed a model to accommodate different population groups: people who inject drugs on substitution therapy with methadone; people who inject opiates and do not take any substitution therapy; and people who do not inject any drugs, hence do not need substitution therapy. The researchers inputted Ukraine country-level data into this model and used current HIV trends in Ukraine to make rational assumptions on possible future trends and scenarios. They considered scenarios expanding methadone substitution therapy availability, increasing acces to ART, or both. Then, the researchers measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost effectiveness for the different scenarios. They found that after 20 years, HIV prevalence reached 67.2% in people who inject drugs and 0.88% in people who do not inject drugs without further interventions. Offering methadone substitution therapy to 25% of people who inject drugs was the most effective strategy in reducing prevalence of HIV and was also the most cost effective, averting 4,700 infections and adding 75,700 QALYs versus the status quo at $530/QALY gained. Expanding both methadone substitution therapy and ART was also a highly cost effective option, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy. Offering ART to 80% of eligible people who did not inject drugs, and 10% of people who injected drugs averted only 1,800 infections, and added 76,400 QALYs at $1,330/QALY gained.
What Do These Findings Mean?
The results show that methadone substitution-focused therapeutic scenarios are the most cost effective, and that benefits increase with the scale of the project, even among people who do not inject drugs. This makes a methadone substitution strategy a highly cost-effective option for addressing the growing HIV epidemic in Ukraine. Therefore, if it is not feasible to invest in large-scale methadone substitution programs for any reason, political circumstances for example, providing as much methadone substitution as is acceptable is still desirable. While substitution therapy appears to avert the most HIV infections, expanded ART provides the largest total increase in QALYs. Thus, methadone substitution therapy and ART offer complementary benefits. Because the HIV epidemic in Ukraine is representative of the HIV epidemic in Eastern Europe and Central Asia, the cost-effective strategies that the researchers have identified may help inform all decision makers faced with a mixed HIV epidemic.
Additional Information
Please access these Web sites via the online version of this summary at
Alliance provides information on its work supporting community action on AIDS in Ukraine
USAID provides an HIV/AIDS Health Profile for Ukraine
UNICEF provides information about its activities to help Ukraine fight rising HIV/AIDS infection rates
International Harm Reduction Association provides information about the status of harm reduction interventions such as methadone substitution therapy around the world
PMCID: PMC3046988  PMID: 21390264
3.  Standard triple therapy for Helicobacter pylori infection in China: A meta-analysis 
World Journal of Gastroenterology : WJG  2014;20(40):14973-14985.
AIM: To assess the efficacy and safety of standard triple therapy compared with other pre-existing and new therapies in China.
METHODS: Literature searches were conducted in the following databases: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the VIP database, the China National Knowledge Infrastructure database, and the Chinese Biomedical Database. A meta-analysis of all randomized controlled trials (RCTs) comparing standard triple therapy for the eradication of Helicobacter pylori with pre-existing and new therapies in China was performed using Comprehensive Meta-Analysis 2.0. There were 49 studies that met our criteria and the qualities of these studies were assessed using the Jadad scale. The Mantel-Haenszel method was used for pooling dichotomous data. We also conducted subgroup analyses according to age, duration of treatment and drug type. Sensitivity analyses and a cumulative meta-analysis were also performed with CMA 2.0. Publication bias was evaluated using Egger’s test, Begg’s test or a funnel plot.
RESULTS: A total of 49 RCTs including 8332 patients were assessed. This meta-analysis showed that standard triple therapy with proton pump inhibitors (PPIs), amoxicillin (AMO) and clarithromycin (CLA) was inferior to sequential therapy [relative risk (RR) = 0.863; 95% confidence interval (CI): 0.824-0.904], but was not superior to quadruple therapy (RR = 1.073; 95%CI: 0.849-1.357) or other triple therapies (RR = 1.01; 95%CI: 0.936-1.089). The meta-analysis also suggested that standard triple therapy is slightly more effective than dual therapy (RR = 1.14; 95%CI: 0.99-1.31). However, the differences were not statistically significant. We removed the only trial with a regimen lasting 14 d by sensitivity analysis and found that 7-d standard triple therapy was superior to 7-d dual therapy (RR = 1.222; 95%CI: 1.021-1.461). Moreover, a sub-analysis based on the duration of quadruple therapy indicated that the 7-d and 10-d standard triple therapies were inferior to sequential therapy (RR = 0.790; 95%CI: 0.718-0.868; RR = 0.917; 95%CI: 0.839-1.002, respectively). Additionally, there were no significant differences in cure rate or adverse events among standard triple therapy, quadruple therapy, and other triple therapies (RR = 0.940; 95%CI: 0.825-1.072; RR = 1.081; 95%CI: 0.848-1.378, respectively). Standard triple therapy had a higher occurrence of side effects than sequential therapy (RR = 1.283; 95%CI: 1.066-1.544).
CONCLUSION: The eradication rates with a standard triple therapy consisting of PPI, AMO, and CLA are suboptimal in China, and new treatment agents need to be developed.
PMCID: PMC4209562  PMID: 25356059
Helicobacter pylori; Eradication; Combination drug therapy; Amoxicillin; Clarithromycin; Adverse effects; Meta-analysis
4.  Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy 
Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings.
Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy.
Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin.
Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.
PMCID: PMC3736972  PMID: 23926315
5.  Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy 
The BMJ  2013;347:f4587.
Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings.
Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy.
Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin.
Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.
PMCID: PMC3736972  PMID: 23926315
6.  Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis 
Rhee, Soo-Yon | Blanco, Jose Luis | Jordan, Michael R. | Taylor, Jonathan | Lemey, Philippe | Varghese, Vici | Hamers, Raph L. | Bertagnolio, Silvia | de Wit, Tobias F. Rinke | Aghokeng, Avelin F. | Albert, Jan | Avi, Radko | Avila-Rios, Santiago | Bessong, Pascal O. | Brooks, James I. | Boucher, Charles A. B. | Brumme, Zabrina L. | Busch, Michael P. | Bussmann, Hermann | Chaix, Marie-Laure | Chin, Bum Sik | D’Aquin, Toni T. | De Gascun, Cillian F. | Derache, Anne | Descamps, Diane | Deshpande, Alaka K. | Djoko, Cyrille F. | Eshleman, Susan H. | Fleury, Herve | Frange, Pierre | Fujisaki, Seiichiro | Harrigan, P. Richard | Hattori, Junko | Holguin, Africa | Hunt, Gillian M. | Ichimura, Hiroshi | Kaleebu, Pontiano | Katzenstein, David | Kiertiburanakul, Sasisopin | Kim, Jerome H. | Kim, Sung Soon | Li, Yanpeng | Lutsar, Irja | Morris, Lynn | Ndembi, Nicaise | NG, Kee Peng | Paranjape, Ramesh S. | Peeters, Martine | Poljak, Mario | Price, Matt A. | Ragonnet-Cronin, Manon L. | Reyes-Terán, Gustavo | Rolland, Morgane | Sirivichayakul, Sunee | Smith, Davey M. | Soares, Marcelo A. | Soriano, Vincent V. | Ssemwanga, Deogratius | Stanojevic, Maja | Stefani, Mariane A. | Sugiura, Wataru | Sungkanuparph, Somnuek | Tanuri, Amilcar | Tee, Kok Keng | Truong, Hong-Ha M. | van de Vijver, David A. M. C. | Vidal, Nicole | Yang, Chunfu | Yang, Rongge | Yebra, Gonzalo | Ioannidis, John P. A. | Vandamme, Anne-Mieke | Shafer, Robert W.
PLoS Medicine  2015;12(4):e1001810.
Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.
Methods and Findings
We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.
Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.
In this individual patient and sequence-level meta-analysis, Soo-Yon Rhee and colleagues measure regional trends in HIV-1 transmitted drug resistance prevalence and investigate the specific mutations responsible for TDR in different regions and in different virus subtypes.
Editors' Summary
About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells and leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within ten years of infection. Then, in 1996, effective antiretroviral (ARV) therapy—drug combinations that suppress HIV replication by inhibiting reverse transcriptase and other essential viral enzymes—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ARV therapy was expensive, HIV/AIDS remained fatal in low- and middle-income countries (LMICs). In 2003, the international community began to work towards achieving universal access to ARV therapy. Now, more than 10 million HIV-positive individuals in LMICs receive ARV therapy, usually as a fixed-dose combination of two nucleoside reverse transcriptase inhibitors (NRTIs), such as tenofovir and lamivudine, plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz or nevirapine.
Why Was This Study Done?
The global scale-up of ARV therapy has reduced deaths from HIV/AIDS and the incidence of HIV infection in LMICs, but the development of resistance to ARV therapy is threatening these advances. HIV rapidly accumulates genetic changes (mutations), some of which make HIV resistant to ARV therapy. Up to 30% of patients receiving a fixed-dose NRTI/NNRTI combination develop virological failure, and a high proportion of these patients develop mutations associated with resistance to the ARVs in their regimen. Moreover, the proportion of newly infected, ARV-naïve individuals with transmitted drug resistance (TDR) is also increasing. Organizations involved in HIV/AIDS control need to understand the regional and temporal mutational patterns of TDR to inform the development of guidelines for first-line ARV therapy and of inexpensive resistance mutation assays for use in LMICs. Here, using a statistical approach called meta-analysis to combine information from individual patients about the resistance mutations they carry, the researchers investigate the molecular epidemiology of TDR (the patterns of molecular changes underlying TDR in populations) and identify the HIV drug-resistance mutations most responsible for TDR in different world regions.
What Did the Researchers Do and Find?
The researchers identified 287 studies published between 2000 and 2013 from 111 countries that included the reverse transcriptase sequences of HIV viruses from 50,870 ARV-naïve, HIV-positive individuals. The researchers analyzed each virus sequence for the presence of 93 surveillance drug-resistance mutations (SDRMs) previously shown to be specific indicators of TDR. Meta-analysis of these data indicated that the average overall prevalence of TDR (the proportion of ARV-naïve, HIV-positive individuals infected with a virus carrying one or more SDRMs) ranged from 2.8% in sub-Saharan Africa to 11.5% in North America. In sub-Saharan Africa, the odds (chance) of TDR increased 1.09-fold per year following national ARV scale-up; this increase was attributable to an increase in NRTI- and NNRTI-associated resistance. By contrast, in LMICs in south/southeast Asia, the odds of TDR remained unchanged following ARV scale-up. In Latin America/Caribbean, North America, Europe, and upper-income Asian countries, the odds of TDR have increased by around 1.10-fold per year since 1995, mainly as a result of increased NNRTI resistance. Four NNRTI-associated and 16 NRTI-associated SDRMs accounted for most NNRTI- and NRTI-associated TDR, respectively, in all regions. Notably, in sub-Saharan Africa and south/southeast Asia, most of the NNRTI-associated SDRMs detected were associated with high-level resistance to nevirapine or efavirenz. Finally, the researchers report that 95% of TDR viruses in sub-Saharan Africa and south/southeast Asia were unrelated and had therefore arisen independently.
What Do These Findings Mean?
Because many drug-resistance mutations reduce HIV’s fitness and tend to be lost rapidly in individuals not exposed to ARV therapy, differences among the datasets used in this meta-analysis with respect to how long each ARV-naïve patient had been infected with HIV before virus sampling may limit the accuracy of these findings. Nevertheless, the finding that most of the TDR strains detected in sub-Saharan Africa and south/southeast Asia arose independently suggests that improved patient adherence to ARV therapy and the use of ARV regimens that contain drugs to which HIV rarely develops resistance (regimens with a high genetic barrier to resistance) should reduce the generation of new ARV-resistant strains and mitigate TDR increases. In addition, the finding that a few NNRTI-resistance mutations were responsible for most cases of transmitted high-level resistance suggests that an inexpensive assay that detects these specific mutations may be useful for pre-therapy screening in LMICs with high TDR levels.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on antiretroviral drugs and on universal access to ARV therapy; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its guidelines on the use of antiretroviral therapy for treating and preventing HIV infection
The UNAIDS World AIDS Day Report 2014 provides up-to-date information about the AIDS epidemic and efforts to halt it, including progress towards universal access to antiretroviral therapy
The Stanford University HIV Drug Resistance Database includes information about surveillance drug-resistant mutations (SDRMs) and an interactive map displaying HIV drug resistance in ARV-naïve populations
PMCID: PMC4388826  PMID: 25849352
7.  Extracorporeal Photophoresis 
Executive Summary
To assess the effectiveness, safety and cost-effectiveness of extracorporeal photophoresis (ECP) for the treatment of refractory erythrodermic cutaneous T cell lymphoma (CTCL) and refractory chronic graft versus host disease (cGvHD).
Cutaneous T Cell Lymphoma
Cutaneous T cell lymphoma (CTCL) is a general name for a group of skin affecting disorders caused by malignant white blood cells (T lymphocytes). Cutaneous T cell lymphoma is relatively uncommon and represents slightly more than 2% of all lymphomas in the United States. The most frequently diagnosed form of CTCL is mycosis fungoides (MF) and its leukemic variant Sezary syndrome (SS). The relative frequency and disease-specific 5-year survival of 1,905 primary cutaneous lymphomas classified according to the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification (Appendix 1). Mycosis fungoides had a frequency of 44% and a disease specific 5-year survival of 88%. Sezary syndrome had a frequency of 3% and a disease specific 5-year survival of 24%.
Cutaneous T cell lymphoma has an annual incidence of approximately 0.4 per 100,000 and it mainly occurs in the 5th to 6th decade of life, with a male/female ratio of 2:1. Mycosis fungoides is an indolent lymphoma with patients often having several years of eczematous or dermatitic skin lesions before the diagnosis is finally established. Mycosis fungoides commonly presents as chronic eczematous patches or plaques and can remain stable for many years. Early in the disease biopsies are often difficult to interpret and the diagnosis may only become apparent by observing the patient over time.
The clinical course of MF is unpredictable. Most patients will live normal lives and experience skin symptoms without serious complications. Approximately 10% of MF patients will experience progressive disease involving lymph nodes, peripheral blood, bone marrow and visceral organs. A particular syndrome in these patients involves erythroderma (intense and usually widespread reddening of the skin from dilation of blood vessels, often preceding or associated with exfoliation), and circulating tumour cells. This is known as SS. It has been estimated that approximately 5-10% of CTCL patients have SS. Patients with SS have a median survival of approximately 30 months.
Chronic Graft Versus Host Disease
Allogeneic hematopoietic cell transplantation (HCT) is a treatment used for a variety of malignant and nonmalignant disease of the bone marrow and immune system. The procedure is often associated with serious immunological complications, particularly graft versus host disease (GvHD). A chronic form of GvHD (cGvHD) afflicts many allogeneic HCT recipients, which results in dysfunction of numerous organ systems or even a profound state of immunodeficiency. Chronic GVHD is the most frequent cause of poor long-term outcome and quality of life after allogeneic HCT. The syndrome typically develops several months after transplantation, when the patient may no longer be under the direct care of the transplant team.
Approximately 50% of patients with cGvHD have limited disease and a good prognosis. Of the patients with extensive disease, approximately 60% will respond to treatment and eventually be able to discontinue immunosuppressive therapy. The remaining patients will develop opportunistic infection, or require prolonged treatment with immunosuppressive agents.
Chronic GvHD occurs in at least 30% to 50% of recipients of transplants from human leukocyte antigen matched siblings and at least 60% to 70% of recipients of transplants from unrelated donors. Risk factors include older age of patient or donor, higher degree of histoincompatibility, unrelated versus related donor, use of hematopoietic cells obtained from the blood rather than the marrow, and previous acute GvHD. Bhushan and Collins estimated that the incidence of severe cGvHD has probably increased in recent years because of the use of more unrelated transplants, donor leukocyte infusions, nonmyeloablative transplants and stem cells obtained from the blood rather than the marrow. The syndrome typically occurs 4 to 7 months after transplantation but may begin as early as 2 months or as late as 2 or more years after transplantation. Chronic GvHD may occur by itself, evolve from acute GvHD, or occur after resolution of acute GvHD.
The onset of the syndrome may be abrupt but is frequently insidious with manifestations evolving gradually for several weeks. The extent of involvement varies significantly from mild involvement limited to a few patches of skin to severe involvement of numerous organ systems and profound immunodeficiency. The most commonly involved tissues are the skin, liver, mouth, and eyes. Patients with limited disease have localized skin involvement, evidence of liver dysfunction, or both, whereas those with more involvement of the skin or involvement of other organs have extensive disease.
Cutaneous T Cell Lymphoma
The optimal management of MF is undetermined because of its low prevalence, and its highly variable natural history, with frequent spontaneous remissions and exacerbations and often prolonged survival.
Nonaggressive approaches to therapy are usually warranted with treatment aimed at improving symptoms and physical appearance while limiting toxicity. Given that multiple skin sites are usually involved, the initial treatment choices are usually topical or intralesional corticosteroids or phototherapy using psoralen (a compound found in plants which make the skin temporarily sensitive to ultraviolet A) (PUVA). PUVA is not curative and its influence on disease progression remains uncertain. Repeated courses are usually required which may lead to an increased risk of both melanoma and nonmelanoma skin cancer. For thicker plaques, particularly if localized, radiotherapy with superficial electrons is an option.
“Second line” therapy for early stage disease is often topical chemotherapy, radiotherapy or total skin electron beam radiation (TSEB).
Treatment of advanced stage (IIB-IV) MF usually consists of topical or systemic therapy in refractory or rapidly progressive SS.
Bone marrow transplantation and peripheral blood stem cell transplantation have been used to treat many malignant hematologic disorders (e.g., leukemias) that are refractory to conventional treatment. Reports on the use of these procedures for the treatment of CTCL are limited and mostly consist of case reports or small case series.
Chronic Graft Versus Host Disease
Patients who develop cGvHD require reinstitution of immunosuppressive medication (if already discontinued) or an increase in dosage and possibly addition of other agents. The current literature regarding cGvHD therapy is less than optimal and many recommendations about therapy are based on common practices that await definitive testing. Patients with disease that is extensive by definition but is indolent in clinical appearance may respond to prednisone. However, patients with more aggressive disease are treated with higher doses of corticosteroids and/or cyclosporine.
Numerous salvage therapies have been considered in patients with refractory cGvHD, including ECP. Due to uncertainty around salvage therapies, Bhushan and Collins suggested that ideally, patients with refractory cGvHD should be entered into clinical trials.
Two Ontario expert consultants jointly estimated that there may be approximately 30 new erythrodermic treatment resistant CTCL patients and 30 new treatment resistant cGvHD patients per year who are unresponsive to other forms of therapy and may be candidates for ECP.
Extracorporeal photopheresis is a procedure that was initially developed as a treatment for CTCL, particularly SS.
Current Technique
Extracorporeal photopheresis is an immunomodulatory technique based on pheresis of light sensitive cells. Whole blood is removed from patients followed by pheresis. Lymphocytes are separated by centrifugation to create a concentrated layer of white blood cells. The lymphocyte layer is treated with methoxsalen (a drug that sensitizes the lymphocytes to light) and exposed to UVA, following which the lymphocytes are returned to the patient. Red blood cells and plasma are returned to the patient between each cycle.
Photosensitization is achieved by administering methoxsalen to the patient orally 2 hours before the procedure, or by injecting methoxsalen directly ino the leucocyte rich fraction. The latter approach avoids potential side effects such as nausea, and provides a more consistent drug level within the machine.
In general, from the time the intravenous line is inserted until the white blood cells are returned to the patient takes approximately 2.5-3.5 hours.
For CTCL, the treatment schedule is generally 2 consecutive days every 4 weeks for a median of 6 months. For cGvHD, an expert in the field estimated that the treatment schedule would be 3 times a week for the 1st month, then 2 consecutive days every 2 weeks after that (i.e., 4 treatments a month) for a median of 6 to 9 months.
Regulatory Status
The UVAR XTS Photopheresis System is licensed by Health Canada as a Class 3 medical device (license # 7703) for the “palliative treatment of skin manifestations of CTCL.” It is not licensed for the treatment of cGvHD.
UVADEX (sterile solution methoxsalen) is not licensed by Health Canada, but can be used in Canada via the Special Access Program. (Personal communication, Therakos, February 16, 2006)
According to the manufacturer, the UVAR XTS photopheresis system licensed by Health Canada can also be used with oral methoxsalen. (Personal communication, Therakos, February 16, 2006) However, oral methoxsalen is associated with side effects, must be taken by the patient in advance of ECP, and has variable absorption in the gastrointestinal tract.
According to Health Canada, UVADEX is not approved for use in Canada. In addition, a review of the Product Monographs of the methoxsalen products that have been approved in Canada showed that none of them have been approved for oral administration in combination with the UVAR XTS photophoresis system for “the palliative treatment of the skin manifestations of cutaneous T-cell Lymphoma”.
In the United States, the UVAR XTS Photopheresis System is approved by the Food and Drug Administration (FDA) for “use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of CTCL in persons who have not been responsive to other therapy.”
UVADEX is approved by the FDA for use in conjunction with UVR XTS photopheresis system for “use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of CTCL in persons who have not been responsive to other therapy.”
The use of the UVAR XTS photopheresis system or UVADEX for cGvHD is an off-label use of a FDA approved device/drug.
Summary of Findings
The quality of the trials was examined.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence.
Cutaneous T Cell Lymphoma
Overall, there is low-quality evidence that ECP improves response rates and survival in patients with refractory erythrodermic CTCL (Table 1).
Limitations in the literature related to ECP for the treatment of refractory erythrodermic CTCL include the following:
Different treatment regimens.
Variety of forms of CTCL (and not necessarily treatment resistant) - MF, erythrodermic MF, SS.
SS with peripheral blood involvement → role of T cell clonality reporting?
Case series (1 small crossover RCT with several limitations)
Small sample sizes.
Response criteria not clearly defined/consistent.
Unclear how concomitant therapy contributed to responses.
Variation in definitions of concomitant therapy
Comparison to historical controls.
Some patients were excluded from analysis because of progression of disease, toxicity and other reasons.
Unclear/strange statistics
Quality of life not reported as an outcome of interest.
The reported CR range is ~ 16% to 23% and the overall reported CR/PR range is ~ 33% to 80%.
The wide range in reported responses to ECP appears to be due to the variability of the patients treated and the way in which the data were presented and analyzed.
Many patients, in mostly retrospective case series, were concurrently on other therapies and were not assessed for comparability of diagnosis or disease stage (MF versus SS; erythrodermic versus not erythrodermic). Blood involvement in patients receiving ECP (e.g., T cell clonality) was not consistently reported, especially in earlier studies. The definitions of partial and complete response also are not standardized or consistent between studies.
Quality of life was reported in one study; however, the scale was developed by the authors and is not a standard validated scale.
Adverse events associated with ECP appear to be uncommon and most involve catheter related infections and hypotension caused by volume depletion.
GRADE Quality of Studies – Extracorporeal Photopheresis for Refractory Erythrodermic Cutaneous T-Cell Lymphoma
Chronic Graft-Versus-Host Disease
Overall, there is low-quality evidence that ECP improves response rates and survival in patients with refractory cGvHD (Table 2).
Patients in the studies had stem cell transplants due to a variety of hematological disorders (e.g., leukemias, aplastic anemia, thalassemia major, Hodgkin’s lymphoma, non Hodgkin’s lymphoma).
In 2001, The Blue Cross Blue Shield Technology Evaluation Centre concluded that ECP meets the TEC criteria as treatment of cGvHD that is refractory to established therapy.
The Catalan health technology assessment (also published in 2001) concluded that ECP is a new but experimental therapeutic alternative for the treatment of the erythrodermal phase of CTCL and cGvHD in allogenic HPTC and that this therapy should be evaluated in the framework of a RCT.
Quality of life (Lansky/Karnofsky play performance score) was reported in 1 study.
The patients in the studies were all refractory to steroids and other immunosuppressive agents, and these drugs were frequently continued concomitantly with ECP.
Criteria for assessment of organ improvement in cGvHD are variable, but PR was typically defined as >50% improvement from baseline parameters and CR as complete resolution of organ involvement.
Followup was variable and incomplete among the studies.
GRADE Quality of Studies – ECP for Refractory cGvHD
As per the GRADE Working Group, overall recommendations consider 4 main factors.
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence (Tables 1 and 2).
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For refractory erythrodermic CTCL, the overall GRADE and strength of the recommendation is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to an annual budget impact of approximately $1.5M Cdn (based on 30 patients) while the cost-effectiveness of ECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness. The device is licensed by Health Canada, but the sterile solution of methoxsalen is not licensed.
With an annual budget impact of $1.5 M Cdn (based on 30 patients), and the current expenditure is $1.3M Cdn (for out of country for 7 patients), the potential cost savings based on 30 patients with refractory erythrodermic CTCL is about $3.8 M Cdn (annual).
For refractory cGvHD, the overall GRADE and strength of the recommendation is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $1.5M Cdn while the cost-effectiveness of ECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness. Both the device and sterile solution are not licensed by Health Canada for the treatment of cGvHD.
If all the ECP procedures for patients with refractory erythrodermic CTCL and refractory cGvHD were performed in Ontario, the annual budget impact would be approximately $3M Cdn.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379535  PMID: 23074497
8.  Measuring Psychological Change during Cognitive Behaviour Therapy in Primary Care: A Polish Study Using ‘PSYCHLOPS’ (Psychological Outcome Profiles) 
PLoS ONE  2011;6(12):e27378.
Psychological outcome measures are evolving into measures that depict progress over time. Interval measurement during therapy has not previously been reported for a patient-generated measure in primary care. We aimed to determine the sensitivity to change throughout therapy, using ‘PSYCHLOPS’ (Psychological Outcome Profiles), and to determine if new problems appearing during therapy diminish overall improvement.
Responses to PSYCHLOPS, pre-, during- and post-therapy were compared. Setting: patients offered brief cognitive behaviour therapy in primary care in Poland.
238 patients completed the pre-therapy questionnaire, 194 (81.5%) the during-therapy questionnaire and 142 the post-therapy questionnaire (59.7%). For those completing all three questionnaires (n = 135), improvement in total scores produced an overall Effect Size of 3.1 (2.7 to 3.4). We estimated change using three methods for dealing with missing values. Single and multiple imputation did not significantly change the Effect Size; ‘Last Value Carried Forward’, the most conservative method, produced an overall Effect Size of 2.3 (1.9 to 2.6). New problems during therapy were reported by 81 patients (60.0%): new problem and original problem scores were of similar magnitude and change scores were not significantly different when compared to patients who did not report new problems.
A large proportion of outcome data is lost when outcome measures depend upon completed end of therapy questionnaires. The use of a during-therapy measure increases data capture. Missing data still produce difficulties in interpreting overall effect sizes for change. We found no evidence that new problems appearing during therapy hampered overall recovery.
PMCID: PMC3240620  PMID: 22194783
9.  Comparative Efficacy of Seven Psychotherapeutic Interventions for Patients with Depression: A Network Meta-Analysis 
PLoS Medicine  2013;10(5):e1001454.
Jürgen Barth and colleagues use network meta-analysis - a novel methodological approach - to reexamine the comparative efficacy of seven psychotherapeutic interventions for adults with depression.
Please see later in the article for the Editors' Summary
Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression.
Methods and Findings
We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = −0.62 to d = −0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = −0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = −0.30, 95% credibility interval [CrI] [−0.54 to −0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [−0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [−0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions.
Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.
Please see later in the article for the Editors' Summary
Editors' Summary
Depression is a very common condition. One in six people will experience depression at some time during their life. People who are depressed have recurrent feelings of sadness and hopelessness and might feel that life is no longer worth living. The condition can last for months and often includes physical symptoms such as headaches, sleeping problems, and weight gain or loss. Treatment of depression can include non-drug treatments (psychotherapy), antidepressant drugs, or a combination of the two. Especially for people with mild or intermediate depression, psychotherapy is often considered the preferred first option. Psychotherapy describes a range of different psychotherapies, and a number of established types of psychotherapies have all shown to work for at least some patients.
Why Was This Study Done?
While it is broadly accepted that psychotherapy can help people with depression, the question of which type of psychotherapy works best for most patients remains controversial. While many scientific studies have compared one psychotherapy with control conditions, there have been few studies that directly compared multiple treatments. Without such direct comparisons, it has been difficult to establish the respective merits of the different types of psychotherapy. Taking advantage of a recently developed method called “network meta-analysis,” the authors re-examine the evidence on seven different types of psychotherapy to see how well they have been shown to work and whether some work better than others.
What Did the Researchers Do and Find?
The researchers looked at seven different types of psychotherapy, which they defined as follows. “Interpersonal psychotherapy” is short and highly structured, using a manual to focus on interpersonal issues in depression. “Behavioral activation” raises the awareness of pleasant activities and seeks to increase positive interactions between the patient and his or her environment. “Cognitive behavioral therapy” focuses on a patient's current negative beliefs, evaluates how they affect current and future behavior, and attempts to restructure the beliefs and change the outlook. “Problem solving therapy” aims to define a patient's problems, propose multiple solutions for each problem, and then select, implement, and evaluate the best solution. “Psychodynamic therapy” focuses on past unresolved conflicts and relationships and the impact they have on a patient's current situation. In “social skills therapy,” patients are taught skills that help to build and maintain healthy relationships based on honesty and respect. “Supportive counseling” is a more general therapy that aims to get patients to talk about their experiences and emotions and to offer empathy without suggesting solutions or teaching new skills.
The researchers started with a systematic search of the medical literature for relevant studies. The search identified 198 articles that reported on such clinical trials. The trials included a total of 15,118 patients and compared one of the seven psychotherapies either with another one or with a common “control intervention”. In most cases, the control (no psychotherapy) was deferral of treatment by “wait-listing” patients or continuing “usual care.” With network meta-analysis they were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of several psychotherapies within the same trial (where those were available) with indirect comparisons across all trials (using no psychotherapy as a control intervention).
Based on the combined trial results, all seven psychotherapies tested were better than wait-listing or usual care, and the differences were moderate to large, meaning that the average person in the group that received therapy was better off than about half of the patients in the control group. When comparing the therapies with each other, the researchers saw small or no differences, meaning that none of them really stood out as much better or much worse than the others. They also found that the treatments worked equally well for different patient groups with depression (younger or older patients, or mothers who had depression after having given birth). Similarly, they saw no big differences when comparing individual with group therapy, or person-to-person with internet-based interactions between therapist and patient.
However, they did find that smaller and less rigorous studies generally found larger benefits of psychotherapies, and most of the studies included in the analysis were small. Only 36 of the studies had at least 50 patients who received the same treatment. When they restricted their analysis to those studies, the researchers still saw clear benefits of cognitive-behavioral therapy, interpersonal therapy, and problem-solving therapy, but not for the other four therapies.
What Do these Findings Mean?
Similar to earlier attempts to summarize and make sense of the many study results, this one finds benefits for all of the seven psychotherapies examined, and none of them stood as being much better than some or all others. The scientific support for being beneficial was stronger for some therapies, mostly because they had been tested more often and in larger studies.
Treatments with proven benefits still do not necessarily work for all patients, and which type of psychotherapy might work best for a particular patient likely depends on that individual. So overall this analysis suggests that patients with depression and their doctors should consider psychotherapies and explore which of the different types might be best suited for a particular patient.
The study also points to the need for further research. Whereas depression affects large numbers of people around the world, all of the trials identified were conducted in rich countries and Western societies. Trials in different settings are essential to inform treatment of patients worldwide. In addition, large high-quality studies should further explore the potential benefits of some of therapies for which less support currently exists. Where possible, future studies should compare psychotherapies with one another, because all of them have benefits, and it would not be ethical to withhold such beneficial treatment from patients.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); information on psychotherapy includes information on its most common forms
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
The UK nonprofit Mind provides information on depression, including an explanation of the most common psychotherapies in the UK
MedlinePlus provides links to other resources about depression (in English and Spanish)
The UK nonprofit has a unique database of personal and patient experiences on depression
PMCID: PMC3665892  PMID: 23723742
10.  A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism 
PLoS Medicine  2007;4(1):e36.
HIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors.
Methods and Findings
We have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy.
HIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy.
Changes in the cleavage site of the Gag substrate for the HIV protease can convey resistance to protease inhibitors and might contribute to virologic failure during therapy that includes these drugs.
Editors' Summary
Twenty-five years ago, infection with the human immunodeficiency virus (HIV)—the causative agent of AIDS—was a death sentence. However, drugs that attack various stages of the HIV life cycle were soon developed that, although not curing the infection, kept it in check when used in combination and greatly increased the life expectancy of people infected with HIV. Unfortunately, viruses resistant to these drugs have rapidly emerged and antiviral therapy now fails in many patients. The use of HIV protease inhibitors (PIs) in combination therapies, for example, has led to the stepwise selection of viral variants resistant to these drugs. Resistance is first acquired when the viral protease changes so that PIs no longer bind to it and inhibit it efficiently. These changes often reduce the efficiency with which the protease binds its substrates—polyproteins called Gag and GagPol that it chops up into smaller proteins to make new viral particles. So the next step is the accumulation of changes elsewhere in the protease that make it work better, and sometimes changes in its substrate that make it easier to cut; these compensatory changes do not directly affect viral resistance to PIs.
Why Was This Study Done?
To prevent viruses with resistance to PIs emerging, drug doses are kept high in patients and new PIs are being developed with high potency against known PI-resistant HIV variants. Both approaches set a “high genetic barrier” to the development of PI resistance by ensuring that HIV has to incorporate many changes in its protease to become resistant. But, the HIV genome naturally changes—mutates—very rapidly, so novel HIV variants could emerge that are less susceptible to the new potent PIs without the virus having to leap this high genetic barrier. In this study, the researchers have investigated whether HIV can find an alternative route to PI resistance that does not involve the introduction of multiple changes into its protease.
What Did the Researchers Do and Find?
The researchers took wild-type HIV and treated it in the laboratory with a new PI regimen that has a high genetic barrier. By gradually increasing its concentration, the researchers selected three viral populations that were able to grow in 4- to 8-fold higher concentrations of the PI than wild-type virus. None of these populations had mutations in the viral protease. Instead, they all had mutations near one of the sites—the NC/p1 site—where the protease normally cuts the Gag polyprotein. These mutations, the researchers report, enhanced the overall efficiency with which the wild-type protease cleaved the polyprotein, and a selection experiment with another PI showed that the development of PI resistance through alterations near the NC/p1 cleavage site was not unique to one PI. The researchers also investigated the potential clinical significance of this new drug resistance mechanism by looking for the same mutations in nearly 30,000 patient samples. Many of the samples did indeed have these mutations. Finally, they showed that mutations at the NC/p1 cleavage site were associated with virological failure (increased viral replication) during PI therapy in an ongoing clinical trial.
What Do These Findings Mean?
These results suggest that increased polyprotein processing because of mutations in the natural substrate of the HIV protease might be a new mechanism by which HIV can become resistant to PIs. This strategy, which occurs in the laboratory and in patients, allows HIV to develop PI resistance without the need for multiple changes in its protease and so avoids the high genetic barrier to resistance that new PIs provide. Clinical studies are now needed to test which of the mutations seen in this study contribute to virological failure, whether the degree of this failure is clinically relevant, and whether these substrate mutations enhance the effect of protease mutations. If the clinical importance of the new mechanism is confirmed, genetic examination of both the polyprotein and the protease will be needed when trying to figure out why a PI-containing therapy is failing in individual patients. Furthermore, it will be necessary to test whether this mechanism can contribute to the development of resistance when evaluating new drugs.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Institute of Allergy and Infectious Diseases factsheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS
US Centers for Disease Control and Prevention information on HIV/AIDS
Aidsmap information on HIV and AIDS provided by the charity NAM
BioAfrica, Bioinformatics for HIV Research, information on HIV-1 protease cleavage sites
PMCID: PMC1769415  PMID: 17227139
11.  Therapy of atopic eczema 
Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany.
This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1].
Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis.
The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of ”basic therapy” - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti-bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti-septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis.
Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The “gold standard” is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients’ education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis.
Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so-called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis.
Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy.
The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults.
The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults.
Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus.
PMCID: PMC3011357  PMID: 21289970
12.  A Descriptive Study of the Practice Patterns of Massage New Zealand Massage Therapists 
Massage therapy has grown in popularity, yet little is known globally or in New Zealand about massage therapists and their practices.
Purpose and Setting:
The aims of this study were to describe the practice patterns of trained Massage New Zealand massage therapists in New Zealand private practice, with regard to therapist characteristics; practice modes and settings, and therapy characteristics; referral patterns; and massage therapy as an occupation.
Research Design and Participants:
A survey questionnaire was mailed to 66 trained massage therapist members of Massage New Zealand who were recruiting massage clients for a concurrent study of massage therapy culture.
Most massage therapists were women (83%), NZ European (76%), and holders of a massage diploma qualification (89%). Massage therapy was both a full- (58%) and part-time (42%) occupation, with the practice of massage therapy being the only source of employment for 70% of therapists. Nearly all therapists (94%) practiced massage for more than 40 weeks in the year, providing a median of 16 – 20 hours of direct client care per week. Most massage therapists worked in a “solo practice” (58%) and used a wide and active referral network. Almost all therapists treated musculoskeletal symptoms: the most common client issues or conditions treated were back pain/problem (99%), neck/shoulder pain/problem (99%), headache or migraine (99%), relaxation and stress reduction (96%), and regular recovery or maintenance massage (89%). The most frequent client fee per treatment was NZ$60 per hour in a clinic and NZ$1 per minute at a sports event or in the workplace. Therapeutic massage, relaxation massage, sports massage, and trigger-point therapy were the most common styles of massage therapy offered. Nearly all massage therapists (99%) undertook client assessment; 95% typically provided self-care recommendations; and 32% combined other complementary and alternative medicine therapies with their massage consultations.
This study provides new information about the practice of massage therapy by trained massage therapists. It will help to inform the massage industry and other health care providers, potential funders, and policymakers about the provision of massage therapy in the NZ health care system.
PMCID: PMC3088528  PMID: 21589692
Complementary and alternative therapies; massage therapy; New Zealand; integrative care; practice patterns
13.  American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma 
In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
PMCID: PMC4757494  PMID: 26428082
Myeloma; Stem cell transplantation; Salvage therapy
14.  Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews 
Two large surveillance studies in adults with asthma have found an increased risk of asthma-related mortality in those who took regular salmeterol as monotherapy in comparison to placebo or regular salbutamol. No similar sized surveillance studies have been carried out in children with asthma, and we remain uncertain about the comparative safety of regular combination therapy with either formoterol or salmeterol in children with asthma.
We have used the paediatric trial results from Cochrane systematic reviews to assess the safety of regular formoterol or salmeterol, either as monotherapy or as combination therapy, in children with asthma.
We included Cochrane reviews relating to the safety of regular formoterol and salmeterol from a search of the Cochrane Database of Systematic Reviews conducted in May 2012, and ran updated searches for each of the reviews. These were independently assessed. All the reviews were assessed for quality using the AMSTAR tool. We extracted the data relating to children from each review and from new trials found in the updated searches (including risks of bias, study characteristics, serious adverse event outcomes, and control arm event rates).
The safety of regular formoterol and salmeterol were assessed directly from the paediatric trials in the Cochrane reviews of monotherapy and combination therapy with each product. Then monotherapy was indirectly compared to combination therapy by looking at the differences between the pooled trial results for monotherapy and the pooled results for combination therapy. The comparative safety of formoterol and salmeterol was assessed using direct evidence from trials that randomised children to each treatment; this was combined with the result of an indirect comparison of the combination therapy trials, which represents the difference between the pooled results of each product when randomised against inhaled corticosteroids alone.
Main results
We identified six high quality, up to date Cochrane reviews. Four of these related to the safety of regular formoterol or salmeterol (as monotherapy or combination therapy) and these included 19 studies in children. We added data from two recent studies on salmeterol combination therapy in 689 children which were published after the relevant Cochrane review had been completed, making a total of 21 trials on 7474 children (from four to 17 years of age). The two remaining reviews compared the safety of formoterol with salmeterol from trials randomising participants to one or other treatment, but the reviews only included a single trial in children in which there were 156 participants.
Only one child died across all the trials, so impact on mortality could not be assessed.
We found a statistically significant increase in the odds of suffering a non-fatal serious adverse event of any cause in children on formoterol monotherapy (Peto odds ratio (OR) 2.48; 95% confidence interval (CI) 1.27 to 4.83, I2 = 0%, 5 trials, N = 1335, high quality) and smaller increases in odds which were not statistically significant for salmeterol monotherapy (Peto OR 1.30; 95% CI 0.82 to 2.05, I2 = 17%, 5 trials, N = 1333, moderate quality), formoterol combination therapy (Peto OR 1.60; 95% CI 0.80 to 3.28, I2 = 32%, 7 trials, N = 2788, moderate quality) and salmeterol combination therapy (Peto OR 1.20; 95% CI 0.37 to 2.91, I2 = 0%, 5 trials, N = 1862, moderate quality).
We compared the pooled results of the monotherapy and combination therapy trials. There was no significant difference between the pooled ORs of children with a serious adverse event (SAE) from long-acting beta2-agonist beta agonist (LABA) monotherapy (Peto OR 1.60; 95% CI 1.10 to 2.33, 10 trials, N = 2668) and combination trials (Peto OR 1.50; 95% CI 0.82 to 2.75, 12 trials, N = 4,650). However, there were fewer children with an SAE in the regular inhaled corticosteroid (ICS) control group (0.7%) than in the placebo control group (3.6%). As a result, there was an absolute increase of an additional 21 children (95% CI 4 to 45) suffering such an SAE of any cause for every 1000 children treated over six months with either regular formoterol or salmeterol monotherapy, whilst for combination therapy the increased risk was an additional three children (95% CI 1 fewer to 12 more) per 1000 over three months.
We only found a single trial in 156 children comparing the safety of regular salmeterol to regular formoterol monotherapy, and even with the additional evidence from indirect comparisons between the combination formoterol and salmeterol trials, the CI around the effect on SAEs is too wide to tell whether there is a difference in the comparative safety of formoterol and salmeterol (OR 1.26; 95% CI 0.37 to 4.32).
Authors’ conclusions
We do not know if regular combination therapy with formoterol or salmeterol in children alters the risk of dying from asthma.
Regular combination therapy is likely to be less risky than monotherapy in children with asthma, but we cannot say that combination therapy is risk free. There are probably an additional three children per 1000 who suffer a non-fatal serious adverse event on combination therapy in comparison to ICS over three months. This is currently our best estimate of the risk of using LABA combination therapy in children and has to be balanced against the symptomatic benefit obtained for each child. We await the results of large on-going surveillance studies to further clarify the risks of combination therapy in children and adolescents with asthma.
The relative safety of formoterol in comparison to salmeterol remains unclear, even when all currently available direct and indirect trial evidence is combined.
PMCID: PMC4022036  PMID: 23076961
Albuterol [administration & dosage; adverse effects; *analogs & derivatives]; Anti-Asthmatic Agents [administration & dosage; *adverse effects]; Asthma [drug therapy; mortality]; Drug Therapy, Combination [methods]; Ethanolamines [administration & dosage; *adverse effects]; Randomized Controlled Trials as Topic; Review Literature as Topic; Child; Humans
15.  Market access pathways for cell therapies in France 
Journal of Market Access & Health Policy  2015;3:10.3402/jmahp.v3.29094.
Introduction and objective
Cell therapies can be classified into three main categories of products: advanced therapy medicinal products (ATMPs), ATMPs prepared on a non-routine basis (hospital exemptions), and minimally manipulated cells. Despite the benefits that cell therapies can bring to patients, they are subject to complex pathways to reach the market in France. The objective of this study was to identify and describe routes to market access for cell therapies in France and how these vary by regulatory status.
The research was structured following five main steps: (1) identification of the French regulatory framework for cell therapies; (2) identification of the health products categorised as cell therapies in France; (3) mapping of the market access pathways per category of cell therapy; (4) validation of findings by interviewing experts; and (5) development of a roadmap summarising market access pathways for cell therapies in France. The secondary research methodology included a comprehensive literature review conducted on websites of French public health institutions, complemented by a research for peer-reviewed articles, abstracts, and grey literature.
Different market access pathways are possible depending on the cell therapy category. For ATMPs, market access pathways depend on the licensing status of the therapy. Licensed ATMPs followed the same market access pathways as ‘conventional’ pharmaceuticals, whereas not-yet-licensed ATMPs can be funded via a specific financial allowance under the framework of a Temporary Authorisation for Use procedure or various research programmes. For new ATMPs that are associated with a separate medical device (not considered as ‘combined ATMPs’) or associated with a new medical procedure, additional pathways will apply for the medical device and/or medical procedure to be reimbursed in the ambulatory settings or at hospital. The most likely funding option for ATMPs prepared on a non-routine basis is outside the diagnosis-related group (DRG) system through Missions of General Interest and Support to Contracting (MIGAC). For minimally manipulated cells, four different funding processes are applicable, depending on the type of activity: (1) inclusion in a DRG; (2) inclusion in the list of products and services qualifying for reimbursement (LPPR) (as a medical device); (3) an annual lump sum provided by regional health agencies; and (4) a financial allowance under Missions of General Interest (MIG).
Cell therapy is a diverse and promising category of medical interventions. Its heterogeneity and complexity mean that several funding options and market access pathways apply. The main challenges facing cell therapies relate to (1) the identification of the most appropriate path to reimbursement, and (2) price setting, whereas high manufacturing costs of these therapies will dictate a high price that could only be achieved by a product that leads to important additional patient benefits compared to available treatment options. More specific funding options could emerge as the number of cell therapies increases and the authorities face the need to structure and stabilise funding. It will be vital for manufacturers to have a clear understanding of the various temporary funding opportunities early in a product's lifecycle for the adoption of a stepwise approach to secure permanent funding. Furthermore, due to the very limited Health Technology Assessment (HTA) bodies experience for cell therapies, manufacturers should enter into dialogues with HTA agencies at an early stage to optimise market access conditions.
PMCID: PMC4802688  PMID: 27123176
France; advanced therapy medicinal products; cell therapy; pricing; reimbursement; market access; funding
16.  New Protease Inhibitors for the Treatment of Chronic Hepatitis C: A Cost-Effectiveness Analysis Author Names 
Annals of internal medicine  2012;156(4):279-290.
Chronic hepatitis C (HCV) is a difficult to treat disease affecting over 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy but are costly. A genetic assay may identify patients most likely to benefit from this treatment advance.
Cost-effectiveness assessment of new protease inhibitors and an Interleukin-28B (IL- 28B) genotyping assay for treating chronic HCV
Decision-analytic Markov model
Data Sources
Published literature and expert opinion
Target Population
Treatment-naïve patients with chronic, genotype 1 HCV mono-infection
Time Horizon
Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy: pegylated interferon with ribavirin; triple therapy: standard therapy and a protease inhibitor). IL-28B guided triple therapy stratifies CC genotype patients to standard therapy and non-CC types to triple therapy.
Outcome Measures
Discounted costs (2010 U.S. dollars) and quality-adjusted life years (QALYs); incremental cost effectiveness ratios
Results of Base-Case Analysis
For patients with mild and advanced fibrosis, universal triple therapy reduces life-time risk of hepatocellular-carcinoma by 39% and 29% and increases quality-adjusted life expectancy by 3% and 8% compared to standard therapy. Gains from IL- 28B guided triple therapy are smaller. If the protease inhibitor costs $1,100 per week, universal triple therapy costs $102,600 per QALY (mild fibrosis) or $51,500 per QALY (advanced fibrosis) compared to IL-28B guided triple therapy and $70,100 per QALY and $36,300 per QALY compared to standard therapy.
Results of Sensitivity Analysis
Results are sensitive to the cost of protease inhibitors and treatment adherence rates.
Lack of long-term comparative effectiveness data on the new protease inhibitors
Both universal triple therapy and IL-28B guided triple therapy are cost-effective with the least expensive protease inhibitor for patients with advanced fibrosis.
Primary Funding Source
Stanford Graduate Fellowship
PMCID: PMC3586733  PMID: 22351713
17.  Effectiveness and Safety of Immunomodulators with Anti-TNF Therapy in Crohn's Disease 
Background & Aims
The benefit of continuing immunomodulators when “stepping up” to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD.
We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared using 3 metrics of effectiveness – surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery – and 2 metrics of safety – serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses.
Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as “step up” after thiopurine therapy. The rates of surgery (hazard ratio [HR] 1.20, 95% CI 0.73-1.96), hospitalization (HR 0.82 [0.57-1.19]), discontinuation of anti-TNF therapy or surgery (HR 1.09, [0.88-1.34]), and serious infection (HR 0.93 [0.88-1.34]) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risk of opportunistic infection (HR 2.64 [1.21-5.73]) and herpes zoster (HR 3.16 [1.25-7.97]) were increased with combination therapy.
We found that continuation of immunomodulators after “stepping up” to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.
PMCID: PMC4475667  PMID: 25724699
thiopurines; infliximab; adalimumab; surgery; hospitalization; infection
18.  Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs 
To analyze patterns of use of adjunctive therapies among new initiators of topical prostaglandin analogs (PGAs) in a managed care population.
The study cohort included patients in a claims database who initiated PGA therapy between June 2007 and April 2011. Patients who had one or more adjunctive therapy prescriptions during 24 months of follow-up were included. Patterns of adjunctive therapy use were identified and compared between patients who had one or two fills of the initial adjunctive therapy and those who had three or more.
There were 16,486 eligible beneficiaries. Of these, 5,933 (36%) had one or more adjunctive therapies within 24 months from the start of the PGA, 82% of whom started adjunctive therapy within 12 months. About 28% of patients started adjunctive therapy with a fixed-combination product; 45% of these patients started within the first 30 days. Overall, a large number of patients (42%) required adjunctive therapy within 30 days. Twenty-five percent of patients had only one or two prescriptions of their initial adjunctive therapy; of these patients, 74% discontinued adjunctive therapy altogether.
Approximately 30% of patients starting glaucoma therapy will require adjunctive therapy within 1 year, and many receive a fixed-combination product as initial adjunctive therapy shortly after starting glaucoma therapy. This suggests a prescribing trend toward earlier, more aggressive drug therapy to control pressure and minimize disease progression. We found that compliance with adjunctive therapy continues to be a problem for patients, which could be attributed to a number of treatment burden and economic factors.
PMCID: PMC4061175  PMID: 24959067
costs and cost analysis; drug therapy; combination; polypharmacy
19.  AB037. Drug-related costs of rhinitis in Australia: a NostraData cross-sectional study of pharmacy ​​purchases​ 
Journal of Thoracic Disease  2016;8(Suppl 5):AB037.
Intranasal corticosteroids (INS) are a first-line therapy for rhinitis according to all international clinical guidelines for rhinitis. Although many added treatments are not recommended, the use of multiple therapies to control symptoms is frequent, as patients often continue to experience debilitating symptoms while on medication. Previous estimates of multiple therapy prescriptions may have been too conservative, as most rhinitis therapies are also available over-the-counter (OTC). This may affect the cost burden of rhinitis treatment. To investigate the extent of multiple therapy use to treat rhinitis in Australia, using doctor prescriptions and OTC medication; and to assess the additional cost incurred by multiple therapy use.
This was a historical cohort study of pharmacy-related claims from NostraData, Australia. We examined all rhinitis therapy purchases (antihistamines, INS, combination treatments of both such as Dymista, non-steroidal nasal sprays, leukotriene receptor antagonists (LTRA), eye drops for allergic conjunctivitis, oral steroids and systemic steroids) from 909 pharmacies, including OTC and prescription drugs. We used therapies purchased at the same transaction to assess the proportion of multiple therapy purchases and their cost.
A total of 4,247,193 pharmacy transactions including rhinitis therapies were analysed; 4% of transactions included multiple rhinitis therapy classes. The average transaction cost was 12.82 EUR for single therapy purchases and 26.72 EUR for multiple therapy purchases. 15% of single therapy purchases were INS, for an average cost of 20.68 EUR. The most frequent additions to INS therapy were antihistamine (74%) and non-steroidal nasal spray (10%). About 94% of antihistamine and 97% of non-steroidal nasal spray purchased as add-on therapy to INS were bought over-the-counter. The average cost of INS & antihistamine and INS & non-steroidal nasal spray transactions was 30.65 and 26.57 EUR, respectively.
Rhinitis patients in Australia frequently purchase OTC antihistamine and non-steroidal nasal spray in addition to the recommended INS therapy. This suggests that INS alone do not provide adequate symptom control. This practice comes at a high financial cost for patients. This study highlights the need for a new and more cost effective treatment option for rhinitis.
PMCID: PMC4958767
Rhinitis; intranasal corticosteroids (INS); costs
20.  Melanoma and immunotherapy bridge 2015 
Nanda, Vashisht G. Y. | Peng, Weiyi | Hwu, Patrick | Davies, Michael A. | Ciliberto, Gennaro | Fattore, Luigi | Malpicci, Debora | Aurisicchio, Luigi | Ascierto, Paolo Antonio | Croce, Carlo M. | Mancini, Rita | Spranger, Stefani | Gajewski, Thomas F. | Wang, Yangyang | Ferrone, Soldano | Vanpouille-Box, Claire | Wennerberg, Erik | Pilones, Karsten A. | Formenti, Silvia C. | Demaria, Sandra | Tang, Haidong | Wang, Yang | Fu, Yang-Xin | Dummer, Reinhard | Puzanov, Igor | Tarhini, Ahmad | Chauvin, Joe-Marc | Pagliano, Ornella | Fourcade, Julien | Sun, Zhaojun | Wang, Hong | Sanders, Cindy | Kirkwood, John M. | Chen, Tseng-hui Timothy | Maurer, Mark | Korman, Alan J. | Zarour, Hassane M. | Stroncek, David F. | Huber, Veronica | Rivoltini, Licia | Thurin, Magdalena | Rau, Tilman | Lugli, Alessandro | Pagès, Franck | Camarero, Jorge | Sancho, Arantxa | Jommi, Claudio | de Coaña, Yago Pico | Wolodarski, Maria | Yoshimoto, Yuya | Gentilcore, Giusy | Poschke, Isabel | Masucci, Giuseppe V. | Hansson, Johan | Kiessling, Rolf | Scognamiglio, Giosuè | Sabbatino, Francesco | Marino, Federica Zito | Anniciello, Anna Maria | Cantile, Monica | Cerrone, Margherita | Scala, Stefania | D’alterio, Crescenzo | Ianaro, Angela | Cirin, Giuseppe | Liguori, Giuseppina | Bott, Gerardo | Chapman, Paul B. | Robert, Caroline | Larkin, James | Haanen, John B. | Ribas, Antoni | Hogg, David | Hamid, Omid | Testori, Alessandro | Lorigan, Paul | Sosman, Jeffrey A. | Flaherty, Keith T. | Yue, Huibin | Coleman, Shelley | Caro, Ivor | Hauschild, Axel | McArthur, Grant A. | Sznol, Mario | Callahan, Margaret K. | Kluger, Harriet | Postow, Michael A. | Gordan, RuthAnn | Segal, Neil H. | Rizvi, Naiyer A. | Lesokhin, Alexander | Atkins, Michael B. | Burke, Matthew M. | Ralabate, Amanda | Rivera, Angel | Kronenberg, Stephanie A. | Agunwamba, Blessing | Ruisi, Mary | Horak, Christine | Jiang, Joel | Wolchok, Jedd | Ascierto, Paolo A. | Liszkay, Gabriella | Maio, Michele | Mandalà, Mario | Demidov, Lev | Stoyakovskiy, Daniil | Thomas, Luc | de la Cruz-Merino, Luis | Atkinson, Victoria | Dutriaux, Caroline | Garbe, Claus | Wongchenko, Matthew | Chang, Ilsung | Koralek, Daniel O. | Rooney, Isabelle | Yan, Yibing | Dréno, Brigitte | Sullivan, Ryan | Patel, Manish | Hodi, Stephen | Amaria, Rodabe | Boasberg, Peter | Wallin, Jeffrey | He, Xian | Cha, Edward | Richie, Nicole | Ballinger, Marcus | Smith, David C. | Bauer, Todd M. | Wasser, Jeffrey S. | Luke, Jason J. | Balmanoukian, Ani S. | Kaufman, David R. | Zhao, Yufan | Maleski, Janet | Leopold, Lance | Gangadhar, Tara C. | Long, Georgina V. | Michielin, Olivier | VanderWalde, Ari | Andtbacka, Robert H. I. | Cebon, Jonathan | Fernandez, Eugenio | Malvehy, Josep | Olszanski, Anthony J. | Gause, Christine | Chen, Lisa | Chou, Jeffrey | Stephen Hodi, F. | Brady, Benjamin | Mortier, Laurent | Hassel, Jessica C. | Rutkowski, Piotr | McNeil, Catriona | Kalinka-Warzocha, Ewa | Lebbé, Celeste | Ny, Lars | Chacon, Matias | Queirolo, Paola | Loquai, Carmen | Cheema, Parneet | Berrocal, Alfonso | Eizmendi, Karmele Mujika | Bar-Sela, Gil | Horak, Christine | Hardy, Helene | Weber, Jeffrey S. | Grob, Jean-Jacques | Marquez-Rodas, Ivan | Schmidt, Henrik | Briscoe, Karen | Baurain, Jean-François | Wolchok, Jedd D. | Pinto, Rosamaria | De Summa, Simona | Garrisi, Vito Michele | Strippoli, Sabino | Azzariti, Amalia | Guida, Gabriella | Guida, Michele | Tommasi, Stefania | Jacquelot, Nicolas | Enot, David | Flament, Caroline | Pitt, Jonathan M. | Vimond, Nadège | Blattner, Carolin | Yamazaki, Takahiro | Roberti, Maria-Paula | Vetizou, Marie | Daillere, Romain | Poirier-Colame, Vichnou | la Semeraro, Michaë | Caignard, Anne | Slingluff, Craig L | Sallusto, Federica | Rusakiewicz, Sylvie | Weide, Benjamin | Marabelle, Aurélien | Kohrt, Holbrook | Dalle, Stéphane | Cavalcanti, Andréa | Kroemer, Guido | Di Giacomo, Anna Maria | Maio, Michaele | Wong, Phillip | Yuan, Jianda | Umansky, Viktor | Eggermont, Alexander | Zitvogel, Laurence | Anna, Passarelli | Marco, Tucci | Stefania, Stucci | Francesco, Mannavola | Mariaelena, Capone | Gabriele, Madonna | Antonio, Ascierto Paolo | Franco, Silvestris | Roberti, María Paula | Enot, David P. | Semeraro, Michaela | Jégou, Sarah | Flores, Camila | Chen, Tseng-hui Timothy | Kwon, Byoung S. | Anderson, Ana Carrizossa | Borg, Christophe | Aubin, François | Ayyoub, Maha | De Presbiteris, Anna Lisa | Cordaro, Fabiola Gilda | Camerlingo, Rosa | Fratangelo, Federica | Mozzillo, Nicola | Pirozzi, Giuseppe | Patriarca, Eduardo J. | Caputo, Emilia | Motti, Maria Letizia | Falcon, Rosaria | Miceli, Roberta | Capone, Mariaelena | Madonna, Gabriele | Mallardo, Domenico | Carrier, Maria Vincenza | Panza, Elisabetta | De Cicco, Paola | Armogida, Chiara | Ercolano, Giuseppe | Botti, Gerardo | Cirino, Giuseppe | Sandru, Angela | Blank, Miri | Balatoni, Timea | Olasz, Judit | Farkas, Emil | Szollar, Andras | Savolt, Akos | Godeny, Maria | Csuka, Orsolya | Horvath, Szabolcs | Eles, Klara | Shoenfeld, Yehuda | Kasler, Miklos | Costantini, Susan | Capone, Francesca | Moradi, Farnaz | Berglund, Pontus | Leandersson, Karin | Linnskog, Rickard | Andersson, Tommy | Prasad, Chandra Prakash | Nigro, Cristiana Lo | Lattanzio, Laura | Wang, Hexiao | Proby, Charlotte | Syed, Nelofer | Occelli, Marcella | Cauchi, Carolina | Merlano, Marco | Harwood, Catherine | Thompson, Alastair | Crook, Tim | Bifulco, Katia | Ingangi, Vincenzo | Minopoli, Michele | Ragone, Concetta | Pessi, Antonello | Mannavola, Francesco | D’Oronzo, Stella | Felici, Claudia | Tucci, Marco | Doronzo, Antonio | Silvestris, Franco | Ferretta, Anna | Guida, Stefania | Maida, Imma | Cocco, Tiziana | Passarelli, Anna | Quaresmini, Davide | Franzese, Ornella | Palermo, Belinda | Di Donna, Cosmo | Sperduti, Isabella | Foddai, MariaLaura | Stabile, Helena | Gismondi, Angela | Santoni, Angela | Nisticò, Paola | Sponghini, Andrea P. | Platini, Francesca | Marra, Elena | Rondonotti, David | Alabiso, Oscar | Fierro, Maria T. | Savoia, Paola | Stratica, Florian | Quaglino, Pietro |  Di Monta, Gianluca | Corrado, Caracò |  Di Marzo, Massimiliano | Ugo, Marone |  Di Cecilia, Maria Luisa | Nicola, Mozzillo | Fusciello, Celeste | Marra, Antonio | Guarrasi, Rosario | Baldi, Carlo | Russo, Rosa |  Di Giulio, Giovanni | Faiola, Vincenzo | Zeppa, Pio | Pepe, Stefano | Gambale, Elisabetta | Carella, Consiglia | Di Paolo, Alessandra | De Tursi, Michele | Marra, Laura | De Murtas, Fara | Sorrentino, Valeria | Voinea, Silviu | Panaitescu, Eugenia | Bolovan, Madalina | Stanciu, Adina | Cinca, Sabin | Botti, Chiara | Aquino, Gabriella | Anniciello, Annamaria | Fortes, Cristina | Mastroeni, Simona | Caggiati, Alessio | Passarelli, Francesca | Zappalà, Alba | Capuano, Maria | Bono, Riccardo | Nudo, Maurizio | Marino, Claudia | Michelozzi, Paola | De Biasio, Valeria | Battarra, Vincenzo C. | Formenti, Silvia | Ascierto, Maria Libera | McMiller, Tracee L. | Berger, Alan E. | Danilova, Ludmila | Anders, Robert A. | Netto, George J. | Xu, Haiying | Pritchard, Theresa S. | Fan, Jinshui | Cheadle, Chris | Cope, Leslie | Drake, Charles G. | Pardoll, Drew M. | Taube, Janis M. | Topalian, Suzanne L. | Gnjatic, Sacha | Nataraj, Sarah | Imai, Naoko | Rahman, Adeeb | Jungbluth, Achim A. | Pan, Linda | Venhaus, Ralph | Park, Andrew | Lehmann, Frédéric F. | Lendvai, Nikoletta | Cohen, Adam D. | Cho, Hearn J. | Daniel, Speiser | Hirsh, Vera
Journal of Translational Medicine  2016;14(Suppl 1):65.
Table of contents
Molecular and immuno-advances
K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma
Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies
K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance
Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini
K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance
Stefani Spranger, Thomas F. Gajewski
K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma
Yangyang Wang, Soldano Ferrone
Combination therapies
K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer
Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria
K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade
Haidong Tang, Yang Wang, Yang-Xin Fu
K7 Biomarkers for treatment decisions?
Reinhard Dummer
K8 Combining oncolytic therapies in the era of checkpoint inhibitors
Igor Puzanov
K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy?
Michael A. Postow
News in immunotherapy
K10 An update on adjuvant and neoadjuvant therapy for melanom
Ahmad Tarhini
K11 Targeting multiple inhibitory receptors in melanoma
Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour
K12 Improving adoptive immune therapy using genetically engineered T cells
David F. Stroncek
Tumor microenvironment and biomarkers
K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression?
Veronica Huber, Licia Rivoltini
K14 Update on the SITC biomarker taskforce: progress and challenges
Magdalena Thurin
World-wide immunoscore task force: an update
K15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathology
Tilman Rau, Alessandro Lugli
K16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patients
Franck Pagès
Economic sustainability of melanoma treatments: regulatory, health technology assessment and market access issues
K17 Nivolumab, the regulatory experience in immunotherapy
Jorge Camarero, Arantxa Sancho
K18 Evidence to optimize access for immunotherapies
Claudio Jommi
Molecular and immuno-advances
O1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCs
Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling
O2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanoma
Giosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone, Stefania Scala, Crescenzo D’alterio, Angela Ianaro, Giuseppe Cirino, Paolo Antonio Ascierto, Giuseppina Liguori, Gerardo Botti
O3 Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the BRIM-3 study
Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Antoni Ribas, David Hogg, Omid Hamid, Paolo Antonio Ascierto, Alessandro Testori, Paul Lorigan, Reinhard Dummer, Jeffrey A. Sosman, Keith T. Flaherty, Huibin Yue, Shelley Coleman, Ivor Caro, Axel Hauschild, Grant A. McArthur
O4 Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma
Mario Sznol, Margaret K. Callahan, Harriet Kluger, Michael A. Postow, RuthAnn Gordan, Neil H. Segal, Naiyer A. Rizvi, Alexander Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda Ralabate, Angel Rivera, Stephanie A. Kronenberg, Blessing Agunwamba, Mary Ruisi, Christine Horak, Joel Jiang, Jedd Wolchok
Combination therapies
O5 Efficacy and correlative biomarker analysis of the coBRIM study comparing cobimetinib (COBI) + vemurafenib (VEM) vs placebo (PBO) + VEM in advanced BRAF-mutated melanoma patients (pts)
Paolo A. Ascierto, Grant A. McArthur, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Ilsung Chang, Daniel O. Koralek, Isabelle Rooney, Yibing Yan, Antoni Ribas, Brigitte Dréno
O6 Preliminary clinical safety, tolerability and activity results from a Phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma
Ryan Sullivan, Omid Hamid, Manish Patel, Stephen Hodi, Rodabe Amaria, Peter Boasberg, Jeffrey Wallin, Xian He, Edward Cha, Nicole Richie, Marcus Ballinger, Patrick Hwu
O7 Preliminary safety and efficacy data from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with advanced/metastatic melanoma
Thomas F. Gajewski, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Jason J. Luke, Ani S. Balmanoukian, David R. Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Tara C. Gangadhar
O8 Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma
Reinhard Dummer, Georgina V. Long, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert H.I. Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas F. Gajewski, John M. Kirkwood, Christine Gause, Lisa Chen, David R. Kaufman, Jeffrey Chou, F. Stephen Hodi
News in immunotherapy
O9 Two-year survival and safety update in patients (pts) with treatment-naïve advanced melanoma (MEL) receiving nivolumab (NIVO) or dacarbazine (DTIC) in CheckMate 066
Victoria Atkinson, Paolo A. Ascierto, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Celeste Lebbé, Lars Ny, Matias Chacon, Paola Queirolo, Carmen Loquai, Parneet Cheema, Alfonso Berrocal, Karmele Mujika Eizmendi, Luis De La Cruz-Merino, Gil Bar-Sela, Christine Horak, Joel Jiang, Helene Hardy, Caroline Robert
O10 Efficacy and safety of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL) who were treated beyond progression in CheckMate 066/067
Georgina V. Long, Jeffrey S. Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Reinhard Dummer, Caroline Robert, Ivan Marquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F. Stephen Hodi, Jedd D. Wolchok
Tumor microenvironment and biomarkers
O11 New biomarkers for response/resistance to BRAF inhibitor therapy in metastatic melanoma
Rosamaria Pinto, Simona De Summa, Vito Michele Garrisi, Sabino Strippoli, Amalia Azzariti, Gabriella Guida, Michele Guida, Stefania Tommasi
O12 Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma and response to ipilimumab
Nicolas Jacquelot, David Enot, Caroline Flament, Jonathan M. Pitt, Nadège Vimond, Carolin Blattner, Takahiro Yamazaki, Maria-Paula Roberti, Marie Vetizou, Romain Daillere, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L Slingluff Jr, Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michaele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel
O13 Serum levels of PD1- and CD28-positive exosomes before Ipilimumab correlate with therapeutic response in metastatic melanoma patients
Passarelli Anna, Tucci Marco, Stucci Stefania, Mannavola Francesco, Capone Mariaelena, Madonna Gabriele, Ascierto Paolo Antonio, Silvestris Franco
O14 Immunological prognostic factors in stage III melanomas
María Paula Roberti, Nicolas Jacquelot, David P Enot, Sylvie Rusakiewicz, Michaela Semeraro, Sarah Jégou, Camila Flores, Lieping Chen, Byoung S. Kwon, Ana Carrizossa Anderson, Caroline Robert, Christophe Borg, Benjamin Weide, François Aubin, Stéphane Dalle, Michele Maio, Jedd D. Wolchok, Holbrook Kohrt, Maha Ayyoub, Guido Kroemer, Aurélien Marabelle, Andréa Cavalcanti, Alexander Eggermont, Laurence Zitvogel
Molecular and immuno-advances
P1 Human melanoma cells resistant to B-RAF and MEK inhibition exhibit mesenchymal-like features
Anna Lisa De Presbiteris, Fabiola Gilda Cordaro, Rosa Camerlingo, Federica Fratangelo, Nicola Mozzillo, Giuseppe Pirozzi, Eduardo J. Patriarca, Paolo A. Ascierto, Emilia Caputo
P2 Anti-proliferative and pro-apoptotic effect of ABT888 on melanoma cell lines and its potential role in the treatment of melanoma resistant to B-RAF inhibitors
Federica Fratangelo, Rosa Camerlingo, Emilia Caputo, Maria Letizia Motti, Rosaria Falcone, Roberta Miceli, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Maria Vincenza Carriero, Giuseppe Pirozzi and Paolo Antonio Ascierto
P3 Involvement of the L-cysteine/CSE/H2S pathway in human melanoma progression
Elisabetta Panza, Paola De Cicco, Chiara Armogida, Giuseppe Ercolano, Rosa Camerlingo, Giuseppe Pirozzi, Giosuè Scognamiglio, Gerardo Botti, Giuseppe Cirino, Angela Ianaro
P4 Cancer stem cell antigen revealing pattern of antibody variable region genes were defined by immunoglobulin repertoire analysis in patients with malignant melanoma
Beatrix Kotlan, Gabriella Liszkay, Miri Blank, Timea Balatoni, Judit Olasz, Emil Farkas, Andras Szollar, Akos Savolt, Maria Godeny, Orsolya Csuka, Szabolcs Horvath, Klara Eles, Yehuda Shoenfeld and Miklos Kasler
P5 Upregulation of Neuregulin-1 expression is a hallmark of adaptive response to BRAF/MEK inhibitors in melanoma
Debora Malpicci, Luigi Fattore, Susan Costantini, Francesca Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto
P6 HuR positively regulates migration of HTB63 melanoma cells
Farnaz Moradi, Pontus Berglund, Karin Leandersson, Rickard Linnskog, Tommy Andersson, Chandra Prakash Prasad
P7 Prolyl 4- (C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy
Cristiana Lo Nigro, Laura Lattanzio, Hexiao Wang, Charlotte Proby, Nelofer Syed, Marcella Occelli, Carolina Cauchi, Marco Merlano, Catherine Harwood, Alastair Thompson, Tim Crook
P8 Urokinase receptor antagonists: novel agents for the treatment of melanoma
Maria Letizia Motti, Katia Bifulco, Vincenzo Ingangi, Michele Minopoli, Concetta Ragone, Federica Fratangelo, Antonello Pessi, Gennaro Ciliberto, Paolo Antonio Ascierto, Maria Vincenza Carriero
P9 Exosomes released by melanoma cell lines enhance chemotaxis of primary tumor cells
Francesco Mannavola, Stella D’Oronzo, Claudia Felici, Marco Tucci, Antonio Doronzo, Franco Silvestris
P10 New insights in mitochondrial metabolic reprogramming in melanoma
Anna Ferretta, Gabriella Guida, Stefania Guida, Imma Maida, Tiziana Cocco, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti, Michele Guida
P11 Lenalidomide restrains the proliferation in melanoma cells through a negative regulation of their cell cycle
Stella D’Oronzo, Anna Passarelli, Claudia Felici, Marco Tucci, Davide Quaresmini, Franco Silvestris
Combination therapies
P12 Chemoimmunotherapy elicits polyfunctional anti-tumor CD8 + T cells depending on the activation of an AKT pathway sustained by ICOS
Ornella Franzese, Belinda Palermo, Cosmo Di Donna, Isabella Sperduti, MariaLaura Foddai, Helena Stabile, Angela Gismondi, Angela Santoni, Paola Nisticò
P13 Favourable toxicity profile of combined BRAF and MEK inhibitors in metastatic melanoma patients
Andrea P. Sponghini, Francesca Platini, Elena Marra, David Rondonotti, Oscar Alabiso, Maria T. Fierro, Paola Savoia, Florian Stratica, Pietro Quaglino
P14 Electrothermal bipolar vessel sealing system dissection reduces seroma output or time to drain removal following axillary and ilio-inguinal node dissection in melanoma patients: a pilot study
Di Monta Gianluca, Caracò Corrado, Di Marzo Massimiliano, Marone Ugo, Di Cecilia Maria Luisa, Mozzillo Nicola
News in immunotherapy
P15 Clinical and immunological response to ipilimumab in a metastatic melanoma patient with HIV infection
Francesco Sabbatino, Celeste Fusciello1, Antonio Marra, Rosario Guarrasi, Carlo Baldi, Rosa Russo, Di Giulio Giovanni, Vincenzo Faiola, Pio Zeppa, Stefano Pepe
P16 Immunotherapy and hypophysitis: a case report
Elisabetta Gambale, Consiglia Carella, Alessandra Di Paolo, Michele De Tursi
Tumor microenvironment and biomarkers
P17 New immuno- histochemical markers for the differential diagnosis of atypical melanocytic lesions with uncertain malignant potential
Laura Marra, Giosuè Scognamiglio, Monica Cantile, Margherita Cerrone, Fara De Murtas, Valeria Sorrentino, Anna Maria Anniciello, Gerardo Botti
P18 Utility of simultaneous measurement of three serum tumor markers in melanoma patients
Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca
P19 The significance of various cut-off levels of melanoma inhibitory activity in evaluation of cutaneous melanoma patients
Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca
P20 The long noncoding RNA HOTAIR is associated to metastatic progression of melanoma and it can be identified in the blood of patients with advanced disease
Chiara Botti, Giosuè Scognamiglio, Laura Marra, Gabriella Aquino, Rosaria Falcone, Annamaria Anniciello, Paolo Antonio Ascierto, Gerardo Botti, Monica Cantile
P21 The effect of Sentinel Lymph Node Biopsy in melanoma mortality: timing of dissection
Cristina Fortes, Simona Mastroeni, Alessio Caggiati, Francesca Passarelli, Alba Zappalà, Maria Capuano, Riccardo Bono, Maurizio Nudo, Claudia Marino, Paola Michelozzi
P22 Epidemiological survey on related psychopathology in melanoma
Valeria De Biasio, Vincenzo C. Battarra
Immunotherapy beyond melanoma
K19 Predictor of response to radiation and immunotherapy
Silvia Formenti
K20 Response and resistance to PD-1 pathway blockade: clues from the tumor microenvironment
Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube and Suzanne L. Topalian
K21 Combination immunotherapy with autologous stem cell transplantation, protein immunization, and PBMC reinfusion in myeloma patients
Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Adeeb Rahman, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Andrew Park, Frédéric F. Lehmann, Nikoletta Lendvai, Adam D. Cohen, and Hearn J. Cho
K22 Anti-cancer immunity despite T cell “exhaustion”
Speiser Daniel
Immunotherapy in oncology (I-O): data from clinical trial
K23 The Checkpoint Inhibitors for the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC)
Vera Hirsh
PMCID: PMC4965835  PMID: 27461275
21.  ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia 
PLoS Pathogens  2007;3(4):e46.
Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50–75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that >80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy.
Author Summary
Combination antiretroviral therapy is effective in reducing, but not eliminating, HIV-1 replication. Residual viremia during suppressive antiretroviral therapy may arise from a number of sources, including reservoirs of long-lived virus-producing cells, or ongoing complete cycles of viral replication. Here, we used a new, more sensitive assay of HIV-1 RNA to measure residual viremia in a large cohort of patients with prolonged suppression on antiretroviral therapy. We found a persistent, stable level of viremia in patients on prolonged therapy that correlated with pretherapy levels of HIV-1. Over 80% of patients had viremia ≥1 copy/ml plasma, and the level of viremia was independent of the drug regimen patients were taking. These data strongly suggest that persistent viremia on antiretroviral therapy is likely derived from reservoirs of long-lived virus-producing cells that are not affected by currently available drugs that target new cycles of viral replication. New antiviral strategies that eradicate this reservoir will be necessary to cure HIV-1 infection.
PMCID: PMC1847689  PMID: 17411338
22.  New-onset diabetes and antihypertensive treatment 
Chronic diseases substantially contribute to the continuous increase in health care expenditures, including type-2 diabetes mellitus as one of the most expensive chronic diseases.
Arterial hypertension presents a risk factor for the development of type-2 diabetes mellitus.
Numerous analyses have demonstrated that antihypertensive therapies promote the development of type-2-diabetes mellitus. Studies indicate, that the application of angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor-blockers (ARB) lead to less new-onset diabetes compared to beta-blockers, diuretics and placebo. Given that beta-blockers and diuretics impair the glucose metabolism, the metabolic effects of different antihypertensive drugs should be regarded; otherwise not only the disease itself, but also antihypertensive therapies may promote the development of new-onset diabetes. Even though, the cost of ACE inhibitors and ARB are higher, the use in patients with metabolic disorders could be cost-effective in the long-term if new-onset diabetes is avoided.
To evaluate which class of antihypertensive agents promote the development or the manifestation of type-2 diabetes mellitus. How high is the incidence of new-onset diabetes during antihypertensive therapy and how is treatment-induced type-2 diabetes mellitus evaluated clinically? Which agents are therefore cost-effective in the long term? Which ethical, social or legal aspects should be regarded?
A systematic literature review was conducted including clinical trials with at least ten participants which reported new-onset diabetes in the course of antihypertensive treatment. The trials had to be published after 1966 (after 2003 for economic publications) in English or German.
A total of 34 clinical publications meet the inclusion criteria. Of these, eight publications focus on the development of diabetes mellitus under treatment with diuretic and/or beta-blockers, six publications focused on ACE inhibitors alone or in combination with calcium-channel-blockers, ten publications on ARB and/or ACE inhibitors with respect to their effects on new-onset diabetes or their preventive aspects. Furthermore, five publications investigate the role of calcium-channel-antagonists in the development of diabetes, and five publications indicate the development of new-onset diabetes with different antihypertensive agents amongst each other or in comparison to no antihypertensive treatment. The clinical trials show a significant difference in the development of new-onset diabetes. Therapies with diuretics and/or beta-blockers result in a higher incidence of new-onset diabetes. ARB as well as ACE inhibitors have a preventive effect and calcium-channel-blockers show a neutral position regarding the development of new-onset diabetes.
Two publications report on economic results. The first one evaluates the cost-effectiveness of ARB alone or in combination with calcium-channel-blockers in comparison to diuretics alone or in combination with beta-blockers. The second publication compares economic outcomes of calcium-channel-blockers and beta-blockers considering the development of new-onset diabetes. Treatment with the ARB candesartan lead to savings in total costs of 549 US-Dollar per patient and in incremental costs of 30,000 US-Dollar per diabetes mellitus avoided. In the second publication, costs to the amount of 18,965 Euro in Great Britain and 13,210 Euro in Sweden are quoted for an avoided event. The treatment with calcium-channel-blockers compared to beta-blockers is proven to be more cost-effective.
No publications were identified regarding ethical, social and legal aspects.
The available meta-analyses allow for a high clinical evidence level. A few studies vary in terms of diabetes definition and study duration. In most of the trials, the incidence of new-onset diabetes is not an endpoint. The evaluation of treatment-induced diabetes mellitus cannot be conducted, due to the lack of sufficient results in the identified literature. The two economic studies do not address all the objectives sufficiently. Ethical, social and legal aspects are discussed but not analysed systematically.
Based on these studies, sufficient evidence to confirm the presumption that diuretics and/or beta-blockers promote the development of new-onset diabetes compared to other antihypertensive agents, especially in patients who are predisposed, is presented with this report. Trials reflecting the clinical relevance of treatment-induced diabetes mellitus compared to existing diabetes mellitus regarding cardiovascular outcomes are required. Also health economic evaluations considering the development of new-onset diabetes should be conducted for the different classes of antihypertensive agents.
PMCID: PMC3010880  PMID: 21289876
diabetes mellitus, type 2; hypertension; Angiotensin-converting enzyme inhibitors; Angiotensin II type receptor blockers; calcium channel blockers; diuretics
23.  New Oral Anticoagulants in Acute Coronary Syndrome: Is There Any Advantage Over Existing Treatments? 
After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still a standard of care, but several new approaches have been investigated.
The present study re-examined the studies published thus far on this topic to evaluate the effectiveness of dual antiplatelet therapy in comparison to some of these new approaches (mainly, ticagrelor + aspirin and dual therapy plus a new oral anticoagulant [NOAC]; i.e., “triple therapy”).
Materials and Methods:
The clinical material was directly derived from that reported in recent meta-analyses. Our re-analysis relied on standard equivalence methods in which interpretation is based on Relative Risks (RRs) along with their 95% Confidence Intervals (CI). The equivalence margins employed in our statistical testing were directly derived from those reported in randomized studies.
The equivalence margins were initially set at RR ranging from 0.775 to 1.29. According to these margins, triple therapy based on any NOAC proved to be superior to dual therapy alone, but at the same time demonstrated its equivalence with dual therapy. The results for apixaban-based triple therapy were inconclusive (not superior, not not-inferior, not equivalent and, of course, not inferior to the controls). Those for rivaroxaban-based triple therapy showed that this combination treatment was superior to dual therapy alone and failed to meet the criterion of equivalence. In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin, the RR was 1 and its 95% CI remained within a post-hoc margin of ± 15%.
Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome.
PMCID: PMC4109037  PMID: 25177676
Anticoagulants; Acute Coronary Syndrome; Rivaroxaban; Ticagrelor
24.  Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”: Napoli, December 3rd–6th 2014 
The fourth “Melanoma Bridge Meeting” took place in Naples, December 3–6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting’s specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.
PMCID: PMC4665874  PMID: 26619946
25.  Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles 
PLoS Computational Biology  2010;6(8):e1000883.
Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents.
Author Summary
A primary obstacle to the success of any anti-HIV treatment is HIV's ability to rapidly resist it by generating new viral strains whose vulnerability to the treatment is reduced. Gene therapies represent a novel class of treatments for HIV infection that may supplement or replace present therapies, as they alleviate some of their major shortcomings. The design of gene therapeutic agents that effectively reduce viral resistance can be aided by a quantitative elucidation of the processes by which resistance is acquired following therapy initiation. We developed a computational model that describes a patient's response to therapy and used it to quantify the influence of therapy parameters and strategies on the development of viral resistance. We find that gene therapy induces different clinical conditions and a much slower viral response than present therapies. These dictate different design principles such as a greater significance to the virus' competence in the absence of therapy. We also show that one can effectively delay emergence of resistance by delivering distinct therapeutic genes into separate cell populations. Our results highlight the differences between traditional and gene therapies and provide a basic understanding of how key controllable parameters and strategies affect resistance development.
PMCID: PMC2920833  PMID: 20711350

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